PMID- 36889064
OWN - NLM
STAT- MEDLINE
DCOM- 20230418
LR  - 20230418
IS  - 2352-3964 (Electronic)
IS  - 2352-3964 (Linking)
VI  - 90
DP  - 2023 Apr
TI  - Peroxisome proliferator-activated receptor ɣ agonist mediated inhibition of 
      heparanase expression reduces proteinuria.
PG  - 104506
LID - S2352-3964(23)00071-3 [pii]
LID - 10.1016/j.ebiom.2023.104506 [doi]
LID - 104506
AB  - BACKGROUND: Proteinuria is associated with many glomerular diseases and a risk 
      factor for the progression to renal failure. We previously showed that heparanase 
      (HPSE) is essential for the development of proteinuria, whereas peroxisome 
      proliferator-activated receptor ɣ (PPARɣ) agonists can ameliorate proteinuria. 
      Since a recent study showed that PPARɣ regulates HPSE expression in liver cancer 
      cells, we hypothesized that PPARɣ agonists exert their reno-protective effect by 
      inhibiting glomerular HPSE expression. METHODS: Regulation of HPSE by PPARɣ was 
      assessed in the adriamycin nephropathy rat model, and cultured glomerular 
      endothelial cells and podocytes. Analyses included immunofluorescence staining, 
      real-time PCR, heparanase activity assay and transendothelial albumin passage 
      assay. Direct binding of PPARɣ to the HPSE promoter was evaluated by the 
      luciferase reporter assay and chromatin immunoprecipitation assay. Furthermore, 
      HPSE activity was assessed in 38 type 2 diabetes mellitus (T2DM) patients before 
      and after 16/24 weeks treatment with the PPARɣ agonist pioglitazone. FINDINGS: 
      Adriamycin-exposed rats developed proteinuria, an increased cortical HPSE and 
      decreased heparan sulfate (HS) expression, which was ameliorated by treatment 
      with pioglitazone. In line, the PPARɣ antagonist GW9662 increased cortical HPSE 
      and decreased HS expression, accompanied with proteinuria in healthy rats, as 
      previously shown. In vitro, GW9662 induced HPSE expression in both endothelial 
      cells and podocytes, and increased transendothelial albumin passage in a 
      HPSE-dependent manner. Pioglitazone normalized HPSE expression in 
      adriamycin-injured human endothelial cells and mouse podocytes, and 
      adriamycin-induced transendothelial albumin passage was reduced as well. 
      Importantly, we demonstrated a regulatory effect of PPARɣ on HPSE promoter 
      activity and direct PPARy binding to the HPSE promoter region. Plasma HPSE 
      activity of T2DM patients treated with pioglitazone for 16/24 weeks was related 
      to their hemoglobin A1c and showed a moderate, near significant correlation with 
      plasma creatinine levels. INTERPRETATION: PPARɣ-mediated regulation of HPSE 
      expression appears an additional mechanism explaining the anti-proteinuric and 
      renoprotective effects of thiazolidinediones in clinical practice. FUNDING: This 
      study was financially supported by the Dutch Kidney Foundation, by grants 15OI36, 
      13OKS023 and 15OP13. Consortium grant LSHM16058-SGF (GLYCOTREAT; a collaboration 
      project financed by the PPP allowance made available by Top Sector Life Sciences 
      & Health to the Dutch Kidney Foundation to stimulate public-private 
      partnerships).
CI  - Copyright (c) 2023 The Author(s). Published by Elsevier B.V. All rights reserved.
FAU - Garsen, Marjolein
AU  - Garsen M
AD  - Department of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud 
      University Medical Center, Nijmegen, the Netherlands.
FAU - Buijsers, Baranca
AU  - Buijsers B
AD  - Department of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud 
      University Medical Center, Nijmegen, the Netherlands.
FAU - Sol, Marloes
AU  - Sol M
AD  - Division of Medical Biology, Department of Pathology and Medical Biology, 
      University Medical Center Groningen, Groningen, the Netherlands.
FAU - Gockeln, Lena
AU  - Gockeln L
AD  - Department of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud 
      University Medical Center, Nijmegen, the Netherlands.
FAU - Sonneveld, Ramon
AU  - Sonneveld R
AD  - Department of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud 
      University Medical Center, Nijmegen, the Netherlands.
FAU - van Kuppevelt, Toin H
AU  - van Kuppevelt TH
AD  - Department of Biochemistry, Radboud Institute for Molecular Life Sciences, 
      Radboud University Medical Center, Nijmegen, the Netherlands.
FAU - de Graaf, Mark
AU  - de Graaf M
AD  - Department of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud 
      University Medical Center, Nijmegen, the Netherlands.
FAU - van den Born, Jacob
AU  - van den Born J
AD  - Division of Nephrology, Department of Internal Medicine, University Medical 
      Center Groningen, Groningen, the Netherlands.
FAU - Kamps, Jan A A M
AU  - Kamps JAAM
AD  - Division of Medical Biology, Department of Pathology and Medical Biology, 
      University Medical Center Groningen, Groningen, the Netherlands.
FAU - van Raalte, Daniel H
AU  - van Raalte DH
AD  - Diabetes Center, VU University Medical Center, Amsterdam, the Netherlands.
FAU - van der Meer, Rutger W
AU  - van der Meer RW
AD  - Department of Radiology, Leiden University Medical Center, Leiden, the 
      Netherlands.
FAU - Lamb, Hildo J
AU  - Lamb HJ
AD  - Department of Radiology, Leiden University Medical Center, Leiden, the 
      Netherlands.
FAU - Hillebrands, Jan-Luuk
AU  - Hillebrands JL
AD  - Division of Pathology, University Medical Center Groningen, Groningen, the 
      Netherlands.
FAU - Rabelink, Ton J
AU  - Rabelink TJ
AD  - Department of Nephrology and Einthoven Laboratory for Vascular Medicine, Leiden 
      University Medical Center, Leiden, the Netherlands.
FAU - Maciej-Hulme, Marissa L
AU  - Maciej-Hulme ML
AD  - Department of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud 
      University Medical Center, Nijmegen, the Netherlands.
FAU - Krenning, Guido
AU  - Krenning G
AD  - Division of Medical Biology, Department of Pathology and Medical Biology, 
      University Medical Center Groningen, Groningen, the Netherlands.
FAU - Nijenhuis, Tom
AU  - Nijenhuis T
AD  - Department of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud 
      University Medical Center, Nijmegen, the Netherlands.
FAU - van der Vlag, Johan
AU  - van der Vlag J
AD  - Department of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud 
      University Medical Center, Nijmegen, the Netherlands. Electronic address: 
      Johan.vanderVlag@radboudumc.nl.
LA  - eng
PT  - Journal Article
DEP - 20230306
PL  - Netherlands
TA  - EBioMedicine
JT  - EBioMedicine
JID - 101647039
RN  - X4OV71U42S (Pioglitazone)
RN  - 0 (PPAR gamma)
RN  - 0 (2-chloro-5-nitrobenzanilide)
RN  - EC 3.2.1.- (heparanase)
RN  - 0 (PPAR-gamma Agonists)
RN  - 0 (Thiazolidinediones)
RN  - 80168379AG (Doxorubicin)
SB  - IM
MH  - Rats
MH  - Mice
MH  - Humans
MH  - Animals
MH  - Pioglitazone/pharmacology/therapeutic use
MH  - PPAR gamma
MH  - *Diabetes Mellitus, Type 2/complications
MH  - PPAR-gamma Agonists
MH  - Endothelial Cells/metabolism
MH  - *Thiazolidinediones/pharmacology/therapeutic use
MH  - Proteinuria/drug therapy/etiology
MH  - *Kidney Diseases/drug therapy
MH  - Doxorubicin/adverse effects
PMC - PMC10043778
OTO - NOTNLM
OT  - Glomerular endothelial cells
OT  - Heparanase
OT  - Peroxisome proliferator-activated receptor ɣ
OT  - Podocytes
OT  - Proteinuria
OT  - Thiazolidinediones
COIS- Declaration of interests The authors declare that there are no conflicts of 
      interest.
EDAT- 2023/03/09 06:00
MHDA- 2023/04/18 06:41
PMCR- 2023/03/06
CRDT- 2023/03/08 18:06
PHST- 2022/09/05 00:00 [received]
PHST- 2023/02/16 00:00 [revised]
PHST- 2023/02/16 00:00 [accepted]
PHST- 2023/04/18 06:41 [medline]
PHST- 2023/03/09 06:00 [pubmed]
PHST- 2023/03/08 18:06 [entrez]
PHST- 2023/03/06 00:00 [pmc-release]
AID - S2352-3964(23)00071-3 [pii]
AID - 104506 [pii]
AID - 10.1016/j.ebiom.2023.104506 [doi]
PST - ppublish
SO  - EBioMedicine. 2023 Apr;90:104506. doi: 10.1016/j.ebiom.2023.104506. Epub 2023 Mar 
      6.